Retinol (Vitamin A) and its derivatives have a long history as active ingredients in cosmetic compositions to improve the overall appearance of the skin. Retinol itself is unstable and is toxic upon excessive use. Long-chain retinyl esters are sometimes preferred because they are more stable and less irritating to the skin. These esters are expected to be readily hydrolyzed in the skin to afford retinol for metabolism and thus efficacy. Depending on the fatty acids, the hydrolysis product may introduce additional benefits too. Besides fatty acids, other structures, with various biological properties, are also desired in retinyl conjugates in order to improve and/or broaden the biological benefits. Thus, a mild and general method is needed to link retinol or other skin care ingredients with interesting structures.
The most commonly used chemical preparation of esters involves the reaction of an alcohol and an acid chloride or anhydride (activated carboxylate) in the presence of a base. Nucleophilic substitution of a carboxylate on an alkyl halide or sulfonate is another effective method, provided that the halide or sulfonate is readily available. In the case of retinyl esters, both routes proved to be suboptimal since retinol and retinyl esters tend to be unstable under these types of reaction conditions.
There have been several reports of chemical and enzymatic syntheses of retinyl esters. The preparation of a retinol-ascorbic acid conjugate has been described in the literature where the two substructures are connected by a glycolate linker using a two-step chemical route. Enzymatic esterification or trans-esterification preparation of retinyl esters are usually catalyzed by native or modified enzymes. These reactions generally only afford incomplete conversion to the desired retinyl ester product unless the by-product is removed from the reaction by the use of a large amount of molecular sieves, using reduced pressure, and/or by purging the reaction mixture with an inert gas. The substrate specificity of many enzymes generally limits this type of transformation to straight-chain carboxylic acids, especially fatty acids. Since the synthesis and hydrolysis of esters are catalyzed by the same family of enzymes, i.e. lipases, esters that cannot be enzymatically prepared are less likely to be readily hydrolyzed by enzymes in the skin to release the active agent retinol. Although in some cases it is possible to esterify retinol by chemical methods with challenging species, such as branched carboxylic acids or other sterically-hindered species, these esters might only offer marginal efficacy since they still need to be hydrolyzed in the skin to release retinol to be effective. Thus, a process for conjugating retinol or other skin care ingredients with a broad variety of species which would release retinol in vivo would be of interest.
A specially-designed linker, which is used to connect skin care ingredients with a variety of species, can be envisioned to solve this challenge. It would be highly desirable that this connection occur under mild conditions and in high yield. This would allow the preparation of conjugates of skin care ingredients and other species that are difficult to directly connect. More importantly, this linker should also facilitate the enzymatic ester hydrolysis and thus the ready release of the free skin care ingredient in the skin.